Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as reductions in hyperlipidemia and hypertension constitute the only treatment strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Reports of the pro-atherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles. Indeed, this is a primary mechanism by which macrophages can degrade excess lipids and cytotoxic materials present in the atherosclerotic plaque. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages suggesting that attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy-lysosomal biogenesis, shows that enhancing TFEB function in macrophages leads to reductions in atherosclerosis of mice. In an attempt to harness this pathway therapeutically, we have uncovered a safe and natural sugar called trehalose, able to induce TFEB and autophagy-lysosome biogenesis in macrophages and recapitulate the atheroprotective properties. This raises the prospect of this sugar as a novel and practical therapy. In specific aim 1, we will dissect the mechanisms linking trehalose to macrophage autophagy- lysosomal biogenesis. In specific aim 2, we will determine the predominant autophagic processes in macrophages that underlie trehalose?s ability to reduce atherosclerosis. A major impediment to the therapeutic use of trehalose is degradation by the enzyme trehalase, present in higher organisms including mammals. In specific aim 3, genetic and pharmacological techniques of inhibiting trehalase will be used to determine if trehalose?s effects can be synergized. This proposal will test the hypothesis that trehalose can harness macrophage autophagy-lysosomal biogenesis to treat atherosclerosis.